Paclitaxel (Taxol®) is a standard and effective chemotherapeutic agent for many cancer types, e.g. ovarian cancer, breast cancer, small cell lung cancer, and non-small cell lung cancer. Because paclitaxel is very insoluble in water, formulation of this drug requires Cremophor EL which causes significant side effects such as allergic reactions. Patients receiving Paclitaxel (PTX) require premedication with histamine blockers and steroid.
Abraxane® is a newer formulation of paclitaxel that has less of these side effects and it is among the first nanotherapeutic agents approved by the FDA. It consists of human serum albumin nanoparticles (˜130 nm) loaded with paclitaxel. However, because of its relatively large size, it is unlikely that Abraxane can penetrate deep into the tumor mass. In addition, these relatively large nanoparticles have a propensity to be trapped in the liver and the reticuloendothelial system (RES). Doxil® or liposomal doxorubicin, another nanotherapeutic drug, has similar dimensions as Abraxane but is coated by polyethylene glycol (PEG). Compared to the parent doxorubicin free drug, Doxil has less cardiotoxicity. Similar to Abraxane, it is doubtful that Doxil can penetrate deep into the tumor mass.
Although these two nanotherapeutics exhibit better clinical toxicity profile, their anti-tumor effects are only marginally better than the original drug formulation Amphiphilic block copolymers can form micelles on the nanoscale and have been applied in the development of drug delivery systems. Amphiphilic block copolymers can form hydrotropic micelles in nanoscale (<100 nm) and have been applied in the development of drug delivery systems. However, most of these micelles are non-biodegradable and tend to be trapped in the RES. Furthermore, these micelles often consist of linear hydrophobic polymers that form a loose core under aqueous environment, leading to instability and low drug loading capacity. There is a need to develop smaller (20-80 nm) stealth and biocompatible micelles as effective nanocarriers for anti-cancer drug delivery in vivo.
We have recently developed several novel nanocarriers for PTX or other hydrophobic drugs. These novel nanocarriers, comprising of PEG and oligo-cholic acids, can self-assemble under aqueous conditions to form core-shell (cholane-PEG) structures that can carry PTX in the hydrophobic interior. These amphiphilic drug-loaded nanoparticles are expected to be therapeutic by themselves with improved clinical toxicity profile. More importantly, when decorated with cancer cell surface targeting ligands and/or tumor blood vessel ligands, these nanocarriers will be able to deliver toxic therapeutic agents to the tumor sites. The final size of the nanocarriers (10 to 100 nm) is tunable by using various, or a combination of, different cholane-PEG preparations. The nanocarriers and their components, PEG and cholic acid, are all non-toxic and fully biocompatible.
PEG has been widely used in various biomedical applications because it is inert and biocompatible. There are a number of PEG-modified protein drugs approved by the FDA, e.g., PEGylated asparagines. PEGylation not only improves the pharmacokinetic properties but also lowers the immunogenicity of protein drugs. Small molecule or peptide drugs, when PEGylated, have been shown to increase their circulation time and delay their metabolism. PEG grafted on the surface of nanoparticles lowers the in vivo extravasation of these particles into normal tissues and reticuloendothelial system (RES). In in vivo imaging studies, PEG modification has been shown to reduce aggregation and toxicities of inorganic nanoparticles, such as quantum dots and magnetic nanoparticles. Bile acids are natural surfactants biosynthesized in the liver of mammals as emulsifiers in the digestion of fats. Cholic acid, a primary component of bile acid, possesses facial amphiphilic structure: a rigid steroid scaffold with four hydrophilic groups on one surface and hydrophobic methyl groups on the other surface of the scaffold. Cholic acid salt form cigar shape micelles in water, and its synthetic oligomers in water forms unimolecular micelle with a hydrophobic pocket, which can thermodynamically seclude hydrophobic molecules. However, the application of the oligo-cholic acid in drug delivery is limited by its poor solubility and low drug loading capacity. We have previously prepared a star-shaped cholic acid-PEG compound with four PEG chains grafted on a single cholic acid core. This compound can form spherical micelles in aqueous solution, and it can be used as a carrier in drug delivery. However, the critical micellation concentration (cmc) of this compound is relative high due to the dominant hydrophilic PEG component compared to the single cholane unit, and the resulting micelles prepared under aqueous condition is relatively big (>200 nm in diameter).
Surprisingly, the present invention meets this, and other needs, by providing a much smaller and more stable nanocarrier with core-shell structure prepared from cholanes on PEG.